NO128070B - - Google Patents

Description

The present invention relates to an analogous process for the production of new, pharmacologically active imidazolidinone derivatives with the general formula I, where X means hydrogen, chlorine, the methyl or methoxy group,

a lower alkyl group with 1-4 carbon atoms,

1*2 hydrogen or the methyl group and

n 2 or 3,

as well as their addition salts with inorganic or organic acids.

Such compounds, especially 1-[2-[4-(8-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-methyl- 2-imidazolidinone and 1-[2-[4-(8-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-methyl- 2-imidazolidinone, as well as their salts possess valuable pharmacological properties and a high therapeutic index. They have a central depressant effect on peroral, rectal or parenteral administration, e.g. they reduce motility, potentiate narcosis, have an antiemetic effect and show an inhibitory effect in the "test de la traction". They also exhibit a sympatholytic, histamine- and serotonin-antagonistic effect. These effective qualities, which can be perceived by selected standard tests [cf. R. Domenjoz and W. Theobald, Arch.Int. Pharmacodyn. 120, 450 (1959) and W. Theobald et al., Arznei-mittelforsch. 17, 561 (1967)], characterizes the compounds as suitable for the treatment of tension and irritation states of various origins.'

In the compounds of the general formula I, R^ can mean lower alkyl groups, e.g. the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.

For the preparation according to the invention of a compound of the general formula I, a compound of the general formula II is reacted,

where X and R have the meaning given under formula I, or an alkali metal derivative of such a compound with a reactive ester of a compound of the general formula

III,

where R^ and n have the meaning given under formula I, and optionally transfer the reaction product with an inorganic or organic acid to an addition salt.

Suitable reactive esters of compounds with it

general formula III is e.g. halogens, such as chlorides or bromides, further sulphonic acid esters, e.g. the methanesulfonic acid ester or the o- or p-toluenesulfonic acid ester.

These esters are reacted with the free base II, preferably in the presence of a solvent. Suitable solvents are those which are inert under the reaction conditions, e.g. hydrocarbons, such as benzene, toluene or xylene, halogen hydrocarbons, such as chloroform, ether-like liquids, such as ether or dioxane, as well as lower alkanones, such as acetone, methyl ethyl ketone or diethyl ketone. The reaction temperatures are between approx. 50 - 150°, preferably at the boiling point of the solvent used.

In the reaction according to the invention of a molar equivalent of reactive ester with a molar equivalent of free base, a molar equivalent of acid is separated. This acid can be bound to excess base with the general formula II or to the dibasic reaction product. Preferably, an acid-binding agent is added to the reaction mixture. Suitable acid binding agents are e.g. alkali metal carbonates, such as sodium or potassium carbonate, further tertiary organic bases, such as e.g. pyridine, triethylamine or N,N-diisopropylethylamine. Excess tertiary bases can also be used as a solvent.

If, in the reaction according to the invention, instead of the free base with the general formula II, an alkali metal derivative of this compound is used, e.g. a sodium, potassium or lithium derivative, then it is advantageous to carry out the reaction in a hydrocarbon, e.g. in benzene or toluene.

The formation of alkali metal derivatives of the first reaction component preferably takes place in situ, e.g. by adding at least one molar equivalent of alkali metal hydride, alkali metal amide or an alkali metal organic compound, when starting from a molar equivalent of free base. E.g. used as alkali metal amide sodium bg iitium amide, as alkali metal hydride sodium hydride and as alkali metal organic compound phenyl lithium or butyl lithium.

Of the starting substances with the general formula II are e.g. 8-chloro-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene described in the literature. The 8-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene can be obtained by another method, e.g. as follows: One starts from 8-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, which is condensed in benzene with 1-piperazine-carboxylic acid ethyl ester to 4-(8-methyl-10 ,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-piperazine-1-carboxylic acid ethyl ester. Finally, a condensation product is hydrolyzed and decarboxylated by heating with potassium hydroxide in ethanol. Other starting substances with the general formula II can be prepared analogously.

The second reaction component according to the method of the invention are the reactive esters of compounds with the general formula III. Of these compounds, e.g. 1-(2-chloro-ethyl)- and 1-(3-chloro-propyl)-3-methyl-2-imidazolidinone as well as 1-(2-chloro-ethyl)-3-butyl-2-imidazolidinone are known and allow produced according to different methods. Other compounds of this type can be prepared analogously.

According to a second method according to the invention, compounds with the general formula I, where symbol n = 2, are obtained when one reacts one compound with the general formula II, where X and R2 have the meanings given under formula I,

or an alkali metal derivative of such a compound with a compound of the general formula IV,

where Y means halogen, and

R2 has the meaning given under formula I, or with an alkali metal derivative of such a compound and optionally transfers the reaction product with an inorganic or organic acid to an addition salt.

The Y residue in the general formula IV is, as a halogen, preferably chlorine or bromine.

The reaction according to the invention of the free base with the general formula II, or its alkali metal derivatives with urea derivatives or their alkali metal derivatives are carried out in the same solvents or diluents and at the same reaction temperatures as in the first method. In the reaction of a molar equivalent of free base with a molar equivalent of free urea derivative, two molar equivalents of halogen hydrogen are split off, which can also be bound to the same acid-binding agents. Both reaction components are used according to the method of the invention as alkali metal derivatives, e.g. as sodium, potassium or lithium derivatives, and then preferably in situ. These alkali metal derivatives can be obtained analogously to the alkali metal derivatives from the first method.

The preparation of starting substances of the general formula II

is explained in connection with the first procedure. A starting substance, which falls under the general formula IV, is. 1-methyl-3,3-bis-(2-chloro-ethyl)-urea, which can be obtained by starting from diethanolamine. With 1-methylisocyanate, the diethanolamine gives 1-methyl-3,3-bis-(2-hydroxyethyl)-urea, which is reacted with thionyl chloride while splitting off sulfur dioxide and hydrogen chloride. Other starting substances with the general formula IV can be prepared analogously.

According to a third method according to the invention, a reactive ester of a compound of the general formula V, where X and R2 have the meaning given under formula I, is reacted with a compound of the general formula VI,

where R 1 and n have the meaning given under formula I, or with an alkali metal derivative of such a compound, and optionally transfers the reaction product with an inorganic or organic acid to an addition salt.

Suitable reactive esters of compounds of the general formula V are e.g. halides, such as chlorides or bromides, further sulfonic acid esters, such as the methanesulfonic acid ester, the o- or p-toluenesulfonic acid ester, or the o-chloro- or p-chloro-benzene sulfonic acid ester.

The reaction according to the invention of the free bases or their alkali metal derivatives with the reactive ester can be carried out in the same solvents or diluents and at the same reaction temperatures as in the first method. During the reaction of a molar equivalent of a free base with a molar equivalent of a reactive ester, a molar equivalent of acid is split off, which can be bound to the same acid-binding agents as in the first method.

Instead of the free bases, their alkali metal derivatives can be used, e.g. sodium, potassium or lithium derivatives, preferably then in situ. These alkali metal derivatives can be obtained analogously to the alkali metal derivatives obtained by the first method.

The starting materials, the reactive esters of the compounds of the general formula V, e.g. 8,10-dichloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, 8-methyl- or 8-methoxy-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene , is described in the literature. Other starting materials of this type can be prepared analogously.

Furthermore, as representatives of the compounds with the general formula VI, e.g. 1-[2-(1-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone, 1-[3-(1-piperazinyl)-prdpyl]-3-methyl-2-imidazolidinone as well as the corresponding 3-ethyl - compound known, and these can be produced according to different methods. Other compounds of this type can be obtained analogously.

The compounds of the general formula I obtained according to the method according to the invention are finally, if desired, transferred in the usual way into their addition salts with inorganic and organic acids. E.g. a solution of a compound of the general formula I in an organic solvent is added to the desired acid as a salt component or a solution of the same. Organic solvents are preferably chosen for the reaction, in which the formed salt is poorly soluble so that it can be separated by filtration. Such solvents are e.g. methanol, acetone, methyl ethyl ketone, acetone-ethanol, methanol-ether or ethanol-ether.

For use as pharmaceuticals, pharmaceutically acceptable acid addition salts can be used instead of free bases, i.e. salts with such acids, whose anions are not toxic at the dosages in question. Furthermore, it is advantageous when the salts used as pharmaceuticals are easily crystallisable and not or only slightly hygroscopic. For salt formation with compounds of the general formula I can. e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid are used.

The following examples explain in more detail the preparation of the new compounds with the general formula I. The temperatures are given in degrees Celsius.

EXAMPLE 1

a) A suspension of 11.7 g (0.040 mol) of 8-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,djcycloheptene is heated,

8.46 g (0.044 mol) of 1-(2-chloro-ethyl)-3-methyl-2-imidazolidinone and 11.0 g (0.08 mol) of potassium carbonate in 80 ml of diethyl ketone for 24 hours under reflux. The reaction mixture is cooled, the precipitate is sucked off, the precipitate is washed with hot acetone and the filtrate is evaporated in vacuo. The residue obtained is taken up in benzene and water, the aqueous phase is separated and the organic phase is extracted with 1-1 methanesulfonic acid. The free base is precipitated from the acidic extract with conc. ammonia and occupies the crude base in benzene. The benzene-containing solution is washed with water, dried over magnesium sulfate and evaporated.

The crystalline residue is recrystallized in a little ethyl acetate-petroleum ether, after which the pure 1-[2-[4-(8-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl ]-ethyl]-3-methyl-2-imidazolidinone exhibits a m.p. of 116 - 117°. Yield is 11.7 g, 70% of the theoretical.

4.2 g (0.01 mol) of the base obtained is dissolved in 20 ml of dry ethyl acetic acid and a solution of 2.32 g (0.02 mol) maleic acid in 10 ml of dry acetone is added. Add 50 ml abs. ether and filter from the precipitated bis-maleate, after-washing it with abs. ether and dry it in vacuo. After recrystallization in a little abs. ethanol-acetic acid ethyl ester ether melting the pure 1-[2-[4-(8-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]- 3-methyl-2-imidazolidinone-bis-maleate at 138 - 140°.

8-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, which is used as starting material, can be prepared in the following manner: b) A solution of 12.1 g is added (0.05 mol) 8-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 80 ml of benzene

23.7 g (0.15 mol) of 1-piperazine carboxylic acid ethyl ester and reflux the solution for 24 hours. The reaction mixture is poured into 200 ml of ice water, 25 ml of 2-N caustic soda is added and the benzene-containing phase is separated. The aqueous phase is shaken out with benzene, the organic phase is washed with water,

dried over magnesium sulphate, the solvent is removed in vacuo and the crude residue is obtained for further use.

c) 12.9 g of the crude product obtained according to b) is dissolved in 50 ml abs; ethanol, the solution is added 10 g (0.15 mol)

potassium hydroxide and the mixture is refluxed for 20 hours.

The reaction solution is cooled, evaporated in a vacuum, water is added to the resulting residue and the base is taken up in benzene. The benzene solution is washed neutrally with water, shaken out with

100 ml of 2-n hydrochloric acid and separate the acidic aqueous phase alkaline with conc. baking soda. The precipitated free base is extracted with benzene, the benzene solution is washed with water,

twere it over magnesium sulfate and evaporate it in vacuo.

The crystalline residue obtained is recrystallized in acetic acid ethyl ester-pentane. The pure 8-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene melts at 95 - 96°.

Yield is 4.4 g, 30% of the theoretical. of bis-methanesulfonate

m.p. 194 - 196°.

EXAMPLE 2

a) Analogous to example 1, the following end product is obtained:

from 11.7 g (0.040 mol) 8-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 8.36 g (0.44 mol) 1-( 3-chloro-propyl)-3-ethyl-2-imidazolidinone 1-[3^[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-propyl ]-3-ethyl-2-imidazolidinone. The bis-maleate's m.p. which is prepared analogously to example 1 a), becomes 113 - 115°. Yield is 21.7 g,

80% of the theoretical.

The starting material used, 1-(3-chloro-propyl)-3-ethyl^2-imidazolidinone, is prepared as follows: b) 15.6 g (0.175 mol) of 2-ethylamino-ethanol are dissolved in 30 ml of abs. methylene chloride. Add to this solution at -5°

0° in the course of 45 minutes a dissolution of 20.9 g (0.175 mol)

(3-chloro-propyl)-isocyanate in 20 ml abs. methylene chloride. The reaction mixture is stirred for 2 hours at 30° and cooled to 0°.

A solution of 21.9 g ( 0.182 mol) thionyl chloride in 20 ml abs. methylene chloride. The reaction mixture is then boiled for 4 hours under reflux and evaporated in vacuo. The residue obtained, the crude 1-ethyl-1-(2-chloro-ethyl)-3-(3-chloro-propyl)-urea, is dried in high vacuum at 70 - 80°.

Yield is 42.0 g of crude product, which corresponds to 39.8 g (100% of

the theoretical) pure connection.

c) 42.0 g of the crude urea derivative obtained according to b) is heated under exclusion of moisture and vigorous stirring, which contains

keeps 39.8 g (0.175 mole) of the pure compound, 3 hours in a bath at 120° and then 6 hours in a bath at 140°.

The crude 1-(3-chloro-propyl)-3-ethyl-2-imidazblidinone was obtained

is distilled in high vacuum, kp. loi - 103 /0.bi torr "(n^ i 1.4868); yield 28.1 g, 84.5% of the theoretical.

EXAMPLE 3

a) 11.9 g (0.049 mol) of 8-methyl-10-chloro-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene are dissolved in 50 ml of abs. benzene and sprinkled with wood

room temperature a solution of 15.6 g (0.073 mol) of 1-[2-(1-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone in 30 ml of absolute benzene and the reaction mixture is refluxed for 20 hours.

The cooled solution is poured into 200 ml of ice water, 20 ml is added

2- n caustic soda<p>g the organic phase is separated. The organic phase is washed with water and extracted with 150 ml 1-1 methanesulfonic acid solution. The aqueous extract is adjusted to pH 13 with conc. baking soda. The precipitated crude base is extracted with benzene, the benzene solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. The residue obtained is crystallized in acetic acid ethyl ester petroleum ether. Pure 1-[2-[4-(8-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-methyl-2 -imidazolidinone melts at 116 - 117°.

The 8-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene used as starting material is obtained as follows: b) 11.2 g (0.05 mol) 8-methyl-10,11 -dihydro-5H-dibenzo[a,d]-cyclohepten-10-ol is dissolved in 50 ml abs. benzene and 5.14 g (0.065 mol) of pyridine are added. A solution of 7.14 g (0.06 mol) thionyl chloride in 25 ml abs. benzene. During the supply of nitrogen and during stirring is kept

o

the reaction mixture for 5 hours at 50 , and then it is poured into 200 ml of ice water. The mixture is extracted with ether-methylene chloride (2:1). The ether-methylene chloride solution is washed with 1-1 hydrochloric acid, 1-1 sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. The crystalline residue, 8-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, melts at 65 - 68°; yield is 11.3 g, 93% of the theoretical.

EXAMPLE 4

2.92 g (0.01 mol) of 8-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene is boiled with 2.80 g (0.014 mol) of crude l- methyl-3,3-bis-(2-chloro-ethyl)-urea and 3.6 g (0.026 mol)

anhydrous potassium carbonate in 36 ml diethyl ketone 12 hours under reflux. After 4 hours as well as after 8 hours of reaction time, a further 2.4 g (0.018 mol) of potassium carbonate are added each time. The reaction mixture is cooled, diluted with ether, filtered and the filtrate evaporated in vacuo. The obtained residue (5.22 g) is taken up in ether, the solution is extracted with 1-n hydrochloric acid,

wash the hydrochloric acid extract with ether and add sodium carbonate in excess. The precipitated free base is taken up in ether, the ether solution is washed with water, dried over sodium sulphate and evaporated. The obtained residue is chromatographed in a sieve with silica gel (Merck®, grain size 0.05 - 0.2 mm), which is impregnated with 0.5-n caustic soda. Chloroform is used as an eluent. The fractions containing the crude product are evaporated. The residue obtained is recrystallized in ethyl acetate-petroleum ether, after which the pure 1-[2-[4-(8-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl ]-ethyl]-3-methyl-2-imidazolidinone melts at 116 - 117°. yield is 2.72 g, 65% of the theoretical.

EXAMPLE 5

Analogously to example la), the following end products are obtained:

a) from 31.2 g (0.1 mol) of 8-chloro-10-(1-piperazinyl)-10,li-dihydro-5H-dibenzo[a,d]cycloheptene and 17.8 g (0.11 mol) 1-(2-chloro-ethyl)-3-methyl-2-imidazolidinone 1-[2-[4-(8-chloro-10,li-dihydro-5H-dibenzo[a,d]cycloheptene-10 -yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone, which melts at 134 - 135°. Yield is 33.6 g, 75% of the theoretical. Bis-methanesulfonate * 1 1/3 the hydrate is recrystallized in abs. ethanol-diethyl ether and melts at 180 - 181°. b) from 31.2 g (0.1 mol) of 8-chloro-10-(1-piperazinyl)-10,11-dihydro-5H-dibenz[a,d]cycloheptene and 20.9 g (0.11 mol ) 1-(3-chloro-propyl)-3-ethyl-2-imidazolidinone crude 1-[3-[4-(8-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10- yl)-1-piperazinyl]-propyl]-3-ethyl-2-imidazolidinone. Yield .37.4 g, is 80% of the theoretical. The bis-maleate is prepared analogously to example la. M.p.: 113 - 115°. c) from 31.2 g (0.1 mol) of 8-chloro-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 24.0 g (0.11 mol ) 1-(3-chloro-propyl)-3-butyl-2-imidazolidinone crude 1-[3-[4-.(8-chloro-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene- 10-[yl)-1-piperazinyl]-propyl]-3-butyl-2-imidazolidinone. Yield is 35.6 g, 73% of the theoretical.

The obtained oily base is dissolved in acetone and ethereal hydrochloric acid is added until a Congo acid reaction is obtained. The precipitated product is filtered off and recrystallized in abs. ethyl alcohol/acetic acid ethyl ester and diethyl ether. The pure 1-[3-[4-(8-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-propyl]-3-butyl-2- imidazolidinone dihydrochloride 2/3 hydrate melts at 195 - 197°.

The 1-(3-chloropropyl)-3-butyl-2-imidazolidinori used as starting product is prepared as follows: d) 19.6 g (0.175 mol) of 2-butylamino-ethanol are dissolved in 30 ml of abs. methylene chloride. This solution is dripped at -5°

to 0° in the course of 45 minutes a solution of 20.9 g (0.175 mol)

(3-chloro-propyl)-isocyanate in 20 ml abs. methylene chloride. The reaction mixture is stirred for 2 hours at 30° and cooled at 0°. A solution of 21.9 g ( 0.182 mol) thionyl chloride in 20 ml abs. methylene chloride. The reaction mixture is then boiled for 4 hours under reflux and evaporated in vacuo. The residue obtained, the crude 1-butyl-1-(2-chloro-ethyl)-3-(3-chloro-propyl)-urea, is dried in a high vacuum at 70 - 80°, and then heated for 3 hours in a bath at 120° and then 6 hours in a bath at 140°. The crude 1-(3-chloro-propyl)-3-butyl-2-imidazolidinone obtained is distilled in high vacuum, bp. 110 - 112°/0.05 torr.

EXAMPLE 6

Analogous to example la) the following compounds are obtained:

a) from 27.8 g (0.1 mol) 10-(1-piperazinyl)-10,li-dihydro-5H-dibenzo[a,djcycloheptene and 17.8 g (0.11 mol) 1-(2 -chloroethyl)-3-methyl-2-imidazolidinone 1-[2-[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3 -methyl-2-imidazolidinone with m.p. 117 - 118°. Yield is 34.3 g, 85%

of the theoretical. The monomaleate (from abs. ethyl alcohol/ diethyl ether) melts at 172 - 173°.

b) from 27.8 g (0.1 mol) 10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 22.4 g (0.11 mol) 1-( 2-chloroethyl)-3-butyl-2-imidazolidinone 1-[2-[4-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-10-yl)-1-piperazinyl]-ethyl] -5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-butyl-2-imidazolidinone with m.p. 86 - 87°. Yield 34.0 g, 76% of theoretical. The mono-maleate (from abs. ethyl alcohol/diethyl ether) melts at

133 - 134°.

c) from 27.8 g (0.1 mol) 10-(1-piperazinyl)-1b;li-dihydro-5H-dibenzo[a,d]cycloheptene and 20.9 g (0.11 mol) 1-( 3-chloro-propyl )-3-ethyl-2-imidazolidinone crude 1-[4-[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]- propyl]-3-ethyl-2-imidazolidinone. Yield 33.7 g, 78% of the theoretical. 1_[3_[4_(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-propyl]-3-ethyl-2-imidazolidinone-bis-maleate " 1/2 H 2 O melts at 104 - 106° (Prepared analogously to Example 1a).

EXAMPLE 7

Analogous to example la) the following compounds are obtained:

a) from 30.8 g (0.1 mol) crude 8-methoxy-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 17.8 g )0.11 moles)

1-(2-chloroethyl)-3-methyl-2-imidazolidinone 1-[2-[4-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1 -piperazinyl]-ethyl]-3-methyl-2-imidazolidinone with m.p. 122 - 123° (from acetic acid ethyl ester/petroleum ether). Yield is 30.4 g, 70% of the theoretical. The bis-maleate melts at 144 - 146° (from abs. ethyl alcohol/diethyl ether);

in

b) from 30.8 g (0.1 mol) crude 8-methoxy-10-(1-piperazinyl)-10,1-dihydro-5H-dibenzo[a,d]cycloheptene and .19.4 g (0 .11 mol) 1-(3-chloropropyl)-3-methyl-2-imidazolidinone crude 1-.[3-[4-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene- 10-yl)-1-piperazinyl]-propyl]-3-methyl-2-imidazplidinone. Yield is 27.8 g, 62%

of the theoretical. The bis-maleate * 3/4 hydrate melts at 106 - 108° (from abs. ethyl alcohol/diethyl ether).

c) The 8-methoxy-10-(1-piperazinyl 1}-10,11-dihydro-5H-dibenzo[a,d]cycloheptene used as starting material f is prepared as

following:

48.0 g (0.2 mol) of 8-methoxy-10-hydroxy-10,11-dihydro-5H-dibenzo [a,d]cycloheptene is dissolved with 20.7 g (0.26 mol) of pyridine in 200 ml chloroform and this solution is added dropwise at 0 - 5° over the course of 45 minutes to a solution of 28.4 g (0.24 mol) of thionyl chloride in 100 ml of benzene. Under the introduction of nitrogen, the reaction mixture is stirred for 2 hours at 45 - 50°, and then

pour the mixture into 1/2 liter of ice water.

After addition of methylene chloride, the organic layer is separated and washed in this order with each 200 ml 1-1 hydrochloric acid, water, saturated sodium bicarbonate solution and water. The organic phase is separated, dried over magnesium sulphate and the solvent is removed in vacuo. The residue, 8-methoxy-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene melts at 84-86°. d) 25.8 g (0.1 mol) of 8-methoxy-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene are boiled with 47.4 g (0.3 mol) of 1-piperazinecarboxylic acid ethyl ester in 200 ml of benzene for 24 hours under reflux. The reaction mixture is poured into 500 ml of ice water and after the addition of 50 ml of 2-N caustic soda, the benzene-containing phase is separated. The aqueous phase is shaken out with benzene, the organic phase is washed with water, dried over magnesium sulphate and the solvent is removed in vacuo. The oily residue obtained is further used in its crude state.

38.0 g of the crude product obtained according to d) is dissolved in 100 ml abs. ethanol, 20 g (0.358 mol) of potassium hydroxide are added and the mixture is refluxed for 20 hours. The reaction solution is evaporated in vacuo and the residue obtained is added to 200 ml of water and 200 ml of benzene. The benzene solution is washed neutral with water, shaken with 200 ml of 2-n hydrochloric acid<p>g the acidic aqueous phase is made alkaline with conc. baking soda. The precipitated free base is extracted with benzene. The benzene solution obtained is washed with water, dried over magnesium sulphate and evaporated in vacuo to dryness. The residue obtained, 8-methoxy-10-(1-piper-azinyl)-10,11-dihydro^5H-dibenzo[a,d]cycloheptene is further used crude. Yield is 10.8 g, 35% of the theoretical.

EXAMPLE 8

a) From 30.8 g (0.1 mol) of the 8-methoxy-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene obtained according to example 7c) and d) and 21.0 g (0.11 mol) of 1-(2-chloro-ethyl)-3-isopropyl-2-imidazolidinone is obtained analogously to example la)

1-[2-[4-(8-Methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-isopropyl-2-imidazolidinone.

Yield is 35.6 g, 77% of the theoretical. The bis-maleate " 3/4 hydrate melts at 125 - 127° (from abs. ethanol/diethyl ether).

The 1-[2-chloroethyl]-3-isopropyl-2-imidazolidinone used as starting material is prepared as follows: b) 105.1 g (1.0 mol) of freshly distilled diethanolamine is dissolved in 1000 ml abs. methylene chloride and added dropwise at 0 - 5° i

run of 1 hour 89.5 g (1.05 mol) isopropyl isocyanate, which is dissolved in 200 ml abs. methylene chloride. The reaction mixture is stirred for 1 hour at room temperature and 1 hour at reflux temperature.

After cooling to 0°, a solution of 250 g (2.1 mol) thionyl chloride in 250 ml of abs. methylene chloride at 0-5°

in the course of 1 hour. The reaction mixture is refluxed for 4 hours and evaporated in vacuo.

The residue obtained, the crude 1-isopropyl-3,3-bis-(2-chloroethyl)-urea, is heated under exclusion of moisture for 3 hours at 120°

and then 6 hours at 140°.

The crude 1-(2-chloroethyl)-3-isopropyl-2-imidazolidinone obtained is distilled in high vacuum. Kp. 0.02/torr = 88-90°, N^<4>= 1.4855.

EXAMPLE 9

Analogous to example la) the following end product is obtained:

a) from 29.2 g (0.1 mol) of crude 5-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 17.8 g (0.11 moles)

1-(2-chloroethyl)-3-methyl-2-imidazolidinone crude 1-[2-[4-(5-methyl-10,11-dihydrop-5H-dibenzo[a,d]cyclohepten-10-yl)- 1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone. Yield 32.6 g, 78% of the theoretical.

The dioxalate ' 2/3 hydrate melts at 120 - 125° (precipitated from acetone/acetic acid ethyl ester and recrystallized from acetone with a little

ethanol/diethyl ether). 1

b) from 2 9.2 g (0.1 mol) of crude 5-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 19.4 g (0, 11 mol) 1-(3-chloropropyl)-3-methyl-2<->imidazolidinone crude 1-[3-[4-(5-methyl-10,li-di hydro-5H-dibenzo[a,d]cycloheptene -10-yl)-1-piperazinyl]-propyl]-3-methyl-2-imidazolidinone. Yield: 35.2 g = 81.2%

of the theoretical. The pure dioxalate (precipitated from acetone/acetic acid ethyl ester and recrystallized from acetone/ethanol/diethyl ether) melts at 162 - 165°.

The. 5-methyl-10-(1-piperazinyl)-10 used as starting material, 11-dihydro-5H-dibenzo[a,d]cycloheptene is prepared as follows: 44.4 g (0.2 mol) 5-methyl-10, 11-dihydro-5H-dibenzo[a,d]-cyclohepten-10-one is dissolved in 500 ml of methanol and a solution of 7.55 g (0.2 mol) of sodium borohydride in 80 ml of water is added dropwise at reflux temperature over the course of 40 minutes . After the addition is complete, the reaction mixture is boiled for 2 hours under reflux and then most of the methanol is removed in vacuo. The residue obtained is poured into 200 ml of ice water, buffered to pH = 7 with 1-1 sodium dihydrogen phosphate solution and 1-1 hydrochloric acid and shake with ether/methylene chloride 2:1. The organic phases are washed with water, dried over magnesium sulphate and the solvent is removed in vacuo. The residue obtained is recrystallized in benzene/petroleum ether. The pure 5-methyl-10-hydroxy-10,11-dihydro-dibenzo[a,d]cycloheptene melts at 89 - 90°. Yield: 90% of the theoretical.

d) 40.3 g (0.18 mol) of 5-methyl-10-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene is dissolved with 18.9 g (6.234 mol) of pyridine

in 200 ml of chloroform and a solution of 25.6 g (0.216 mol) of thionyl chloride in 100 ml of benzene is added dropwise at 0 - 5°.

Under the introduction of nitrogen, the reaction mixture is stirred for 2 hours at 45 - 50°, and then the mixture is poured into 1/2 liter of ice water. After adding methylene chloride, the organic matter is separated

layer and wash neutrally in this order with every 200 ml l-n

hydrochloric acid, water, saturated sodium bicarbonate solution and water.

The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo at 45°. The residue obtained, the oily 5-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene, is further used crude. Yield: 43.5 g, 100% of it

theoretical.

e) 43.5 g (0.18 mol) of the crude 5-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene obtained according to example 9d)

is boiled for 20 hours under reflux with a solution of 85.5 g (0.54 mol) 1-piperazine carboxylic acid ethyl ester in 400 ml of benzene. The reaction mixture is poured into 500 ml of ice water and after the addition of 100 ml of 2-N caustic soda, the benzene-containing phase is separated, and the aqueous phase is shaken off with benzene. The combined benzene-containing solutions are washed with water, dried over magnesium sulfate and the solvent is removed in vacuo. The oily residue obtained is further used raw.

66.0 g of the crude product obtained above is dissolved in 200 ml abs. ethanol, 40 g of potassium hydroxide are added and the resulting reaction mixture is refluxed for 20 hours.

While the reaction solution is hot, the precipitated potassium carbonate is separated, the residue is washed with hot ethanol and the combined filtrate is evaporated in vacuo to syrup. The residue obtained is added in turn to 300 ml of benzene and 300 ml of water, the benzene-containing phase is separated and washed neutrally with water. After shaking with 400 ml of 2-n hydrochloric acid, the acidic aqueous solution is made alkaline with conc. caustic soda and the base obtained is extracted with benzene. The benzene-containing solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. The residue obtained, 5-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene is further used crude. Yield: 52.5 g, 40% of the theoretical.

EXAMPLE 10

Analogous to example la) the following end products are obtained:

a) from 30.6 g (0.1 mol) crude 5,8-dimethyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 17.8 g (0 .11 moles)

1-(2-chloroethyl)-3-methyl-2-imidazolidinone crude 1-[2-[4-(5,8-dimethyl-10.,H-dihydro-5H-dibenzo[a,d]cycloheptene-10- yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone. Yield 30.2 g, 70% of the theoretical. The dioxalate " 2/3 hydrate (precipitated from acetone/, diethyl ether. and recrystallized from acetic acid ethyl ester with a little alcohol/ diethyl ether) melts at 162 - 168°.

b) from 30.6 g (0-1 mol) crude 5,8-dimethyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibénzo[a,d]cycloheptene and 19.4 g (0.11 moles)

1-(3-chloropropyl)-3-methyl-2-imidazolidinone crude 1-[3-[4-(5,8-dimethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl )-1-piperazinyl]-propyl]-3-methyl-2-imidazolidinone. Yield 32.2 g, 72%

of the theoretical. The dioxalate " 1/3 hydrate melts at 198 - 200°.

The crude 5,8-dimethyl-10-thi-piperazinyl )-10,11-dihydro-5H-dibenzo[a,d]cycloheptene used as the extraction product is obtained analogously to example 9c) - e) from 5,8-dimethyl-10 ,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-one (m.p. 99° in diethyl ether) over the following intermediates: c^) 5,8-dimethyl-10-hydroxy-10,11-dihydro-5H -dibenzp[a,d]

cycloheptene. Temp. 87 - 94° from methylcyclohexane/pentane.

c2) 5,8-dimethyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as crude product.

EXAMPLE 11

Analogous to example 4, the following end products are obtained:

a) from 3.1 g (0.01 mol) of 8-chloro-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2.80 g (0.14 mol ) 1-methyl-3,3-bis(2-chloroethyl)-urea l-[2-[4-(8-chloroT10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1 -piperazinyl]-ethyl]-3-methyl-2-imidazolidinone with m.p. 134 - 135°. Yield 2.4 g = 60% of the theoretical. b) from 2.7 g (0.01 mol) 10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2.80 g (0.14 mol) l-methyl -3,3-bis-(2-chloroethyl)-urea l-[2-[4-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-10-yl)-1-piperazinyl]- ethyl]-3-methyl-2-imidazolidinone with m.p. 117 - 118°. Yield 2.82 g, 70% of the theoretical. c) from 3.08 g (0.01 mol) of crude 8-methoxy-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2.80 g (0.014 mol)

l-methyl-3,3-bis(2-chloroethyl)-urea l-[2-[4-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)- 1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone with m.p. 122 - 123° (from acetic acid ethyl ester/petroleum ether). Yield 2.95 g, 68% of the theoretical.

d) from 2.92 g (0.01 mol) of crude 5-methyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2.8 g (0.014 mol)

1-methyl-3,3-bis-(2-chloroethyl)-urea 2.63 g crude 1-[2-[4-(5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene -10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone, which with oxalic acid gives the dioxalate 2/3 hydrate with m.p. 120 - 125° (from acetic acid ethyl ester/ethanol-diethyl ether).

e) from 3.06 g (0.01 mol) crude 5,8-dimethyl-10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2.80 g (0.014 moles)

1-methyl-3,3-bis-(2-chloroethyl)-urea 2.55 g crude 1-[2-[4-(5,8-dimethyl-10,11-dihydro-5H-dibenzo[a,d ]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone which with oxalic acid gives the dioxalate 2/3 hydrate with m.p. 162 - 168°.

EXAMPLE 12

Analogous example 4 is obtained from:

a) 3.08 g (0.01 mol) crude 8-methoxy-10-(1-piperazinyl)-10,li-dihydro-5H-dibenzo[a,d]cycloheptene and 3.18 g (0.014 mol) 1-isopropyl-3,3-bis-(2-chloroethyl)-urea 2.92 g l-[2-[4-(8-methoxy-10,1l-dihydro-5H-dibenzo[a,d]cycloheptene- 10-yl)-1-piperazinyl]-ethyl]-3-isopropyl-2-imidazolidinone, which with maleic acid (precipitated from acetone/diethyl ether and recrystallized from ethanol/diethyl ether) gives the bis-maleate 3/4 hydrate with m.p. 125 - 127°.

The 1-isopropyl-3,3-bis(2-chloro-ethyl)-urea used as starting product is obtained as follows: b) 10.5 g (0.1 mol) of freshly distilled diethanolanin is dissolved in 100 ml of abs. methylene chloride and added dropwise at 0 - 5° in the run

of 30 min. 8.95 g (0.105 mol) of isopropyl isocyanate, which is dissolved in 20 ml of abs. methylene chloride. The reaction mixture is stirred 1

hour at room temperature and 1 hour at reflux temperature.

After cooling, a solution of 25.0 g (0.21 mol) thionyl chloride in 25 ml of abs. methylene chloride at 0-5°. The reaction mixture is boiled for 4 hours under reflux, evaporated to dryness in vacuo and dried in high vacuum at 40°. The residue obtained, the oily 1-isopropyl-3,3-bis(2-chloroethyl)-urea, is further used crude.

EXAMPLE 13

Analogous to example 4, the following is obtained:

a) from 2.7 g (0.01 mol) 10-(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 3.37 g (0.014 mol) 1-butyl-3 ,3-bis(2-chloroethyl)-urea l-[2-[4-(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]- 3-butyl-2-imidazolidinone with m.p. 86 - 87° (from acetic acid ethyl ester/petroleum ether). Yield is 2.99 g, 67% of the theoretical.

The 1-butyl-3,3-bis-(2-chloro-ethyl)-urea used as starting material is obtained analogously to example 12b) from: b) 10.5 g (0.1 mol) freshly distilled diethanolamine and 10.4 g (0.105 mol) of butyl isocyanate with 25.0 g (0.21 mol) of thionyl chloride. The residue obtained, the oily 1-butyl-3,3-bis(2-chloro-ethyl D-urea) is further used crude.

EXAMPLE 14

Analogous to example 3a), the following end products are obtained:

a) from 13.2 g (0.05 mol) 8,10-dichloro-10,11-dihydro-5H-dibenzo [a,d]cycloheptene and 15.9 g (0.075 mol) 1-[2-(1 -piperazinyl)-ethyl]-3-methyl-2-imidazolidinone 1-[2-[4-(8-klpr-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1- piperazinyl]-ethyl]-3-methyl-2-imidazolidinone with m.p. 134 - 135°. Yield is 6.55 g, 30%

of the theoretical. Bis-methanesulfonate " 1 1/3 hydrate, m.p.

180 - 181° from ethanol/diethyl ether.

b) from 11.4 g (0.05 mol) 10-chloro-10,11-dihydro-5H-dibenzoI-[a,d]cycloheptene and 15.9 g (0.075 mol) 1-[2-(1- piperazinyl)-ethyl]-3-methyl-2-imidazolidinone 1-[2-[4T(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl] -3-methyl-2-imidazolidinone with m.p. 117 - 118°. Yield is 9.3 g, 46% of the theoretical. Monomaleate m.p. 172 - 173° (in ethanol/diethyl ether). c) from 12.9 g (0.05 mol) crude 8-methoxy-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 15.9 g (0.075 mol) l-[2 -thi-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone 1-[2-[4-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl) -1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone with m.p. 122 - 123°. Yield 8.7 g, 48% of the theoretical. The bis-maleate melts at 144 - 146° (in ethanol/diethyl ether). d) from 13.2 g (0.05 mol) 8,10-dichloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 18.0 g (0.075 mol) 1-[3 -tri-piperazinyl)-propyl]-3-ethyl-2-imidazolidinone crude 1-[3-[4-(8-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl )-1-piperazinyl]-propyl]-3-ethyl-2-imidazolidinone. Yield is 7.7 g, 33% of the theoretical. The bis-maleate melts at 113 - 115° (in abs. ethanol/diethyl ether). e) from 11.4 g (0.05 mol) 10-chloro-10,11-dihydro.o-5H-dibenzo-[a,d]cycloheptene and 18.0 g (0.075 mol) 1-[3-( 1-piperazinyl)-propyl]-3-ethyl-2-imidazolidinone crude 1-[3-[4-(10,11-dihydro-dibenzo-pha ,d]-cyclohepten-10-yl)-1-piperazinyl] - propyl]-3-ethyl-2-imidazolidinone. Yield 10.4 g is 48% of the theoretical. The bis-maleate ' 1/2 hydrate melts at 104 - 106° (in acetone with a little ethanol/diethyl ether). f) from 12.9 g (0.05 mol) 8-methoxy-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 17.0 g (0.075 mol) 1^[3- (1^piperazinyl)-propyl)-3-methyl-2-imidazblidinone crude 1-[3-[4-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl) -1-piperazinyl-propyl]-3-methyl-2-imidazolidinone. Yield is 9.65 g, 43% of the theoretical. The bis-maleate * 3/4 hydrate melts at 106 - 108° (in ethanol/diethyl ether). g) from 11.4 g (0.05 mol) 10-chloro-10,11-dihydro-5H-dibenzo[a,d] cycloheptene and 19.0 g (0.075 mol) 1-[2-(1-piperazinyl) )-ethyl]-3-butyl-2-imidazolidinone 1-[2-[4-[10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl] -3-butyl-2-imidazolidinone with m.p. 86 - 87° (from acetic acid ethyl ester/petroleum ether), yield is 8.9 g, 40% of the theoretical.

EXAMPLE 15

Analogously to example 3a), the following end product is obtained:

a) from 13.2 g (0.05 mol) 8,10-dichloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 20.1 g (0.075 mol) 1-(3-thi- piperazinyl)-propyl]-3-butyl-2-imidazolidinone crude 1-[3-[4-(8-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-^yl)- 1-piperazinyl]-propyl]-3-butyl-2-imidazolidinone, yield is 7.65 g, 31% of theory.

The dihydrochloride<*>2/3 hydrate melts at 195 - 197° (in ethanol/acetic acid ethyl ester/diethyl ether).

The 1-[3-(1-piperazinyl)-propyl]-3-butyl-2-imidazolidinone used as starting product is obtained as follows: b) 218 g (1.0 mol of the 1-(3- chloropropyl)-3-butyl-2-imidazolidinone is dissolved with 175 g (1.1 mol)

1-piperazine carboxylic acid ethyl ester in 1000 ml of diethyl ketone and boiled while adding 304 g (2.0 mol) of potassium carbonate for 24 hours under reflux. The reaction mixture is filtered hot, the 1 residue obtained is boiled twice with 500 ml each of chloroform and filtered off. The combined filtrates are evaporated to dryness i

vacuum and the oily residue is distilled in high vacuum.

The pure 1-[3-(4-ethoxycarbonyl-1-piperazinyl)-propyl]-3-butyl-2-imidazolidinone boils at 180 - 210 o /0.01 torr nD 24<=>1.4946. Yield 266 g = 78% of the theoretical.

c) 340.4 g (1.0 mol) of 1-[3-(4-ethoxycarbonyl-1-piperazinyl)-propyl]-3-butyl-2-imidazolidinone is added to a solution

of 300 g potassium hydroxide in 1500 ml abs. ethanol and boil 16

hours during backflow. The precipitate is filtered off and washed out with hot ethanol.

The combined filtrates are evaporated extensively in vacuo, and the residue obtained is taken up in 1000 ml of benzene and 300 ml of water. The aqueous phase is separated, saturated with potassium carbonate and shaken four times with benzene. The combined benzene solutions are dried over potassium carbonate and the solvent is removed in vacuo.

The residue obtained is distilled under high vacuum, whereby the pure 1-[3-(1-piperazinyl)-propyl]-3-butyl-2-imidazolidinone boils at

145 - 150°/0.01 torr. n^<4>= 1.5006. Yield is 250 g, 93%

of the theoretical.

EXAMPLE 16

Analogously to example 3a), the following end product is obtained:

a) from 12.9 g (0.05 mol) crude 8-methoxy-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 18.0 g (0.075 mol) l-[2 -(1-piperazinyl)-ethyl]-3-isopropyl-2-imidazolidinone crude 1-[2-[4-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl )-1-pip-erazinyl]-ethyl]-3-isopropyl-2-imidazolidinoh, yield is 10.1 g, 44% of theory. The bis-maleate " 3/4 hydrate melts at 125 - 127° (in abs. ethanol/diethyl ether).

The 1-[2-(1-piperazinyl)-ethyl]-3-isopropyl-2-imidazolidinone used as starting product is obtained analogously to example 15b) and c).

b) 190.6 g (1.0 mol) of the 1-(2-chloroethyl)-3-isopropyl-2-imidazolidinone obtained according to example 8b) and 175 g (1.1 mol) 1-piperazinecarboxylic acid ethyl ester give 280 g 1-[2-[4-ethoxy-carbonyl-1-pyr<p>erazin<y>1]-et<y>l]-3-isopropyl-2-imidazolidinori as crude residue, which after removal of a pre-fraction (bp. = 140-190°/0.01 torr) has been obtained in high vacuum. From this, 158 g of 1-[2-(1-piperazinyl)-ethyl]-3-isopropyl-2-imidazolidinone are obtained by saponification. Yield = 73%, bp = 150-155°/0.01 torr n^<4>= 1.5034.

EXAMPLE 17

Analogous to example 3a), the following end products are obtained:

a) from 12.1 g (0.05 mol) of the crude 5-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene obtained according to example 9d) and

15.9 g (0.075 mol) 1-[2-(1-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone crude 1-[2-[4-(5-methyl-10,11-dihydro-5H -dibenzo-[α,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone, yield 7.2 g, 37% of theory. The dioxalate 2/3 hydrate melts at 120 - 125° (in acetic acid ethyl ester with a little ethanol/diethyl ether).

b) from 12.1 g (0.05 mol) of that obtained according to example 9d)

crude 5-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and

17.0 g (0.075 mol) 1-[3-(1-piperazinyl)-propyl]-3-methyl-2-imidazolidinone crude 1-[3-[4-(5-methyl-10,11-dihydro-5H -dibenzo-[α,d]cyclohepten-10-yl)-1-piperazinyl]-propyl]-3-methyl-2-imidazolidinone. Yield 7.55 g, 35% of the theoretical.

The dioxalate melts at 162 - 165° (in abs. ethanol/diethyl ether). c) from 12.8 g (0.05 mol) crude 5,8-dimethyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 15.9 g-(0.075 mol) l-[2-(1-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone crude l-[2-[4-(5,8-dimethyl-10,11-dihydro-5H-dibenzo[a,d ]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone. Yield 6.9 g,

32% of the theoretical.

The dioxalate " 2/3 hydrate melts, at 162'- 168° (from ethanol/ethyl acetate/ether). d) from 12.8 g (0.05 mol) crude 5,8-dimethyl-10-chloro-10,11 -dihydro-5H-dibenzo[a,d]cycloheptene and 17.0g (0.075 mol) l-[3-(1-piperazinyl)propyl]-3-methyl-2-imidazolidinone crude l-[3-[4- ( 5,8-dimethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-propyl]-3-methyl-2-imidazolidinone, yield 8.5 g,

38% of the theoretical.

The dioxalate • 1/3 hydrate melts at 198 - 200° (from a little abs. ethanol/acetic acid ethyl ester/diethyl ether).

Claims (1)

1. Analogy method for the production of new, pharmacologically active imidazolidinone derivatives with that gene special formula I, where X means hydrogen, chlorine, methyl or methoxy the group, a lower alkyl group with 1-4 carbon atoms, hydrogen or the methyl group and n 2 or 3, as well as their addition salts with inorganic or organic acids, characterized by a) reacting a compound with the general formula II, where X and R2 have the meaning given under formula I, or an alkali metal derivative of such a compound with a reactive ester of a compound of the general formula III, where R^ and n have the meaning given under formula I, that moon b) reacts a compound with the general formula II defined in claim 1, where X and R2 have the meanings given in formula I, or an alkali metal derivative of such a compound with a compound of the general formula IV, where Y means halogen, and R^ has the one specified in claim 1 under formula I importance, or with an alkali metal derivative of such a compound, or that one c) reacts a reactive ester of a compound with the general formula V, where X and R^ have the meanings given in formula I, with a compound of the general formula VI, where R and n have the meanings given under formula I, or with an alkali metal derivative of such a compound, and after which the reaction product obtained is optionally treated with an inorganic or organic acid in an addition salt.